Yongjing Li,Jiaxun Wan,Fang Wang,Jia Guo,Changchun Wang
The clinical applications of particulate drug delivery systems have demonstrated limited treatment outcomes, which is largely attributable to the elimination of such systems by the immune system, especially in the liver. Inspired by the mechanism of nanomaterial clearance by the liver, we designed a new anticancer auxiliary delivery system by introducing norepinephrine loaded poly(acrylic acid) nanogels as angiotonics. The auxilliary system effectively decreased the liver uptake of nanodrugs by increasing the liver blood flow rate. With administration of the as-prepared norepinephrine-loaded poly(acrylic acid) nanogels, the blood perfusion amount increased significantly by 177.0% (i.e. 2.77 times) as observed directly by ultrasonic imaging, indicating an increased blood flow rate in the liver. Since the blood flow rate plays a key role in nanomaterial clearance in the liver, nanodrug clearance should be changed by modulation of the blood flow. Our in vivo experimental results clearly showed the enhancement of nanodrug efficiency with this two-step treatment, with a 52% improvement in plasma drug concentration, obvious drug accumulation in the tumor, and significant antitumor effects. These results indicate that a pre-conditioning strategy involving norepinephrine-loaded poly(acrylic acid) nanogels can serve as an ideal route for reducing nanodrug clearance by the liver.
Polymer micelles are one of the most investigated nanocarriers for drug delivery; many have entered clinical trials and some are in clinic use, but their delivery systems have not yet shown the expected high therapeutic efficacy in clinics. Further understanding their in vivo behaviors, particularly how quickly and by what mechanism polymer micelles are cleared (i.e., via micelles or unimers) once injected, is key to solving this dilemma. Herein, we hope to answer these questions for the clinically relevant polyethylene glycol-block-poly(ε-caprolactone) (PEG-PCL) and PEG-block-poly(d,l-lactide) (PEG-PDLLA) micelles. A small fraction of the hydrophobic chain ends was conjugated with a pair of fluorescence resonance energy transfer (FRET) dyes, Cy5 and Cy5.5, and used to fabricate FRET micelles whose FRET efficiency was correlated to the percentage of polymer chains in the micelles, the micelle degree. In vitro, serum proteins induced PEG-PCL micelle dissociation to some extent; mouse serum or blood surprisingly did not induce micelle dissociation but once with shear applied by a microfluidic channel caused most PEG-PCL micelles dissociated. After intravenous administration in mice, the PEG-PCL or PEG-PDLLA micelles were quickly sequestered into the liver as unimers, and the micelle degree in the blood quickly decreased to about 20%. The FRET-imaging experiments showed that in blood vessels the micelles quickly dissociated into unimers, which were found associated with albumin in blood and in liver. Thus, it is concluded that, upon intravenous injection, the shear and the bloodborne proteins (particularly albumin) induced the most (∼80%) PEG-PCL and PEG-PDLLA micelles to quickly dissociate into unimers, which were sequestered by Kupffer cells, while intact micelles were difficult to clear. These micelles were able to penetrate tumors and were very stable with cell membranes, but dissociated gradually inside cells. These findings on in vivo micelle fate and the clearance mechanism are directional for the rational design of polymer micelles for improved therapeutics; particularly, improving micelle stability in blood is the prerequisite for surface functionalizations such as introducing targeting ligands.
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